tbuckley/cabot-search huggingface dataset:
Influence of active versus placebo control on treatment responses in randomised controlled trials in rheumatoid arthritis
Authors: Andreas Kerschbaumer, Nina Maria Stimakovits, Josef S Smolen, Tijen Stefanova, Eva Chwala, Daniel Aletaha
Journal: Annals of the Rheumatic Diseases (2023)

Objectives To investigate whether treatment effects of pharmaceutical compounds compared with placebo controls are systematically different to the effects of the same compounds compared with active treatment controls in rheumatoid arthritis (RA) clinical trials. Methods We systematically identified randomised controlled trials (RCTs) in RA, and matched active treatment arms with comparable regimens, populations, background therapy, and outcome reporting, by the nature of their control group (active comparator or placebo). Medline, EMBASE and CENTRAL were used to identify RCTs investigating disease modifying anti-rheumatic drug therapies until December 2021. Using mixed-model logistic regression we estimated OddsRatios (OR) for achieving an American College of Rheumatology (ACR) 20/50/70% response at weeks 12 and 24. Risk of bias was assessed using the Cochrane Tool. Results We screened 8328 studies and included 40 for analysis after detailed review of 590 manuscripts; unique compounds had significantly higher responses in active comparator trials compared with their effects observed in placebo controlled trials, with ORs of 1.67 (95% CI 1.46 to 1.91; p&lt;0.001) for ACR20, 1.50 (95% CI 1.29 to 1.75; p&lt;0.001) for ACR50 and 1.65 (95% CI 1.30 to 2.10; p&lt;0.001) for ACR70 (week 12); corresponding ORs for ACR 20, 50, and 70 (week 24) were 1.93 (95% CI 1.50 to 2.48; p&lt;0.001), 1.75 (95% CI 1.32 to 2.33; p&lt;0.001) and 1.68 (95% CI 1.21 to 2.34; p&lt;0.001), respectively. Sensitivity analyses showed consistent results. Conclusion Placebo controlled trials lead to smaller effect sizes of active compounds in RCTs compared with the same compound in head-to-head trials. This difference may be explained by potential nocebo effects in placebo-controlled settings and needs to be considered when interpreting head-to-head and placebo-controlled trials, by patients, investigators, sponsors and regulatory agencies.
Discovery, development, and clinical proof of mechanism of LY3463251, a long-acting GDF15 receptor agonist
Authors: Olivier Benichou, Tamer Coskun, Malgorzata D. Gonciarz, Parag Garhyan, Andrew C. Adams, Yu Du, James D. Dunbar, Jennifer A. Martin, Kieren J. Mather, Richard T. Pickard, Vincent L. Reynolds, Deborah A. Robins, Simbarashe P. Zvada, Paul J. Emmerson
Journal: Cell Metabolism (2023)

GDF15 and its receptor GFRAL/RET form a non-homeostatic system that regulates food intake and body weight in preclinical species. Here, we describe a GDF15 analog, LY3463251, a potent agonist at the GFRAL/RET receptor with prolonged pharmacokinetics. In rodents and obese non-human primates, LY3463251 decreased food intake and body weight with no signs of malaise or emesis. In a first-in-human study in healthy participants, single subcutaneous LY3463251 injections showed a safety and pharmacokinetic profile supporting further clinical development with dose-dependent nausea and emesis in a subset of individuals. A subsequent 12-week multiple ascending dose study in overweight and obese participants showed that LY3463251 induced significant decreases in food intake and appetite scores associated with modest body weight reduction independent of nausea and emesis (clinicaltrials.gov: NCT03764774). These observations demonstrate that agonism of the GFRAL/RET system can modulate energy balance in humans, though the decrease in body weight is surprisingly modest, suggesting challenges in leveraging the GDF15 system for clinical weight-loss applications.
Tissue resident iNKT17 cells facilitate cancer cell extravasation in liver metastasis via interleukin-22
Authors: Anastasios D. Giannou, Jan Kempski, Ahmad Mustafa Shiri, Jöran Lücke, Tao Zhang, Lilan Zhao, Dimitra E. Zazara, Filippo Cortesi, Kristoffer Riecken, Maria Carolina Amezcua Vesely, Jun Siong Low, Hao Xu, Eleanna Kaffe, Laura Garcia-Perez, Theodora Agalioti, Yoshito Yamada, Wolfgang Jungraithmayr, Ehud Zigmond, Karl-Frederick Karstens, Babett Steglich, Jonas Wagner, Leonie Konczalla, Antonella Carambia, Kornelius Schulze, Johann von Felden, Peter May, Daria Briukhovetska, Tanja Bedke, Leonie Brockmann, Sarah Starzonek, Tobias Lange, Claudia Koch, Sabine Riethdorf, Penelope Pelczar, Marius Böttcher, Morsal Sabihi, Francis J. Huber, Matthias Reeh, Julia Kristin Grass, Ramez Wahib, Hannes Seese, Björn-Ole Stüben, Mohammad Fard-Aghaie, Anna Duprée, Pasquale Scognamiglio, Gabriel Plitzko, Jan Meiners, Shiwa Soukou, Agnes Wittek, Caroline Manthey, Ioannis C. Maroulis, Petra C. Arck, Daniel Perez, Bin Gao, Sotirios G. Zarogiannis, Till Strowig, Renata Pasqualini, Wadih Arap, Javier Suárez Gosálvez, Sebastian Kobold, Immo Prinz, Andreas H. Guse, Michael Tachezy, Tarik Ghadban, Asmus Heumann, Jun Li, Nathaniel Melling, Oliver Mann, Jakob R. Izbicki, Klaus Pantel, Udo Schumacher, Ansgar W. Lohse, Richard A. Flavell, Nicola Gagliani, Samuel Huber
Journal: Immunity (2023)

During metastasis, cancer cells invade, intravasate, enter the circulation, extravasate, and colonize target organs. Here, we examined the role of interleukin (IL)-22 in metastasis. Immune cell-derived IL-22 acts on epithelial tissues, promoting regeneration and healing upon tissue damage, but it is also associated with malignancy. Il22-deficient mice and mice treated with an IL-22 antibody were protected from colon-cancer-derived liver and lung metastasis formation, while overexpression of IL-22 promoted metastasis. Mechanistically, IL-22 acted on endothelial cells, promoting endothelial permeability and cancer cell transmigration via induction of endothelial aminopeptidase N. Multi-parameter flow cytometry and single-cell sequencing of immune cells isolated during cancer cell extravasation into the liver revealed iNKT17 cells as source of IL-22. iNKT-cell-deficient mice exhibited reduced metastases, which was reversed by injection of wild type, but not Il22-deficient, invariant natural killer T (iNKT) cells. IL-22-producing iNKT cells promoting metastasis were tissue resident, as demonstrated by parabiosis. Thus, IL-22 may present a therapeutic target for prevention of metastasis.
Bispecific PD1-IL2v and anti-PD-L1 break tumor immunity resistance by enhancing stem-like tumor-reactive CD8+ T cells and reprogramming macrophages
Authors: Mélanie Tichet, Stephan Wullschleger, Agnieszka Chryplewicz, Nadine Fournier, Rachel Marcone, Annamaria Kauzlaric, Krisztian Homicsko, Laura Codarri Deak, Pablo Umaña, Christian Klein, Douglas Hanahan
Journal: Immunity (2023)

Immunotherapies have shown remarkable, albeit tumor-selective, therapeutic benefits in the clinic. Most patients respond transiently at best, highlighting the importance of understanding mechanisms underlying resistance. Herein, we evaluated the effects of the engineered immunocytokine PD1-IL2v in a mouse model of de novo pancreatic neuroendocrine cancer that is resistant to checkpoint and other immunotherapies. PD1-IL2v utilizes anti-PD-1 as a targeting moiety fused to an immuno-stimulatory IL-2 cytokine variant (IL2v) to precisely deliver IL2v to PD-1+ T cells in the tumor microenvironment. PD1-IL2v elicited substantial infiltration by stem-like CD8+ T cells, resulting in tumor regression and enhanced survival in mice. Combining anti-PD-L1 with PD1-IL2v sustained the response phase, improving therapeutic efficacy both by reprogramming immunosuppressive tumor-associated macrophages and enhancing T cell receptor (TCR) immune repertoire diversity. These data provide a rationale for clinical trials to evaluate the combination therapy of PD1-IL2v and anti-PD-L1, particularly in immunotherapy-resistant tumors infiltrated with PD-1+ stem-like T cells.
Role of MR1-driven signals and amphiregulin on the recruitment and repair function of MAIT cells during skin wound healing
Authors: Anastasia du Halgouet, Aurélie Darbois, Mansour Alkobtawi, Martin Mestdagh, Aurélia Alphonse, Virginie Premel, Thomas Yvorra, Ludovic Colombeau, Raphaël Rodriguez, Dietmar Zaiss, Yara El Morr, Hélène Bugaut, François Legoux, Laetitia Perrin, Selim Aractingi, Rachel Golub, Olivier Lantz, Marion Salou
Journal: Immunity (2023)

Tissue repair processes maintain proper organ function following mechanical or infection-related damage. In addition to antibacterial properties, mucosal associated invariant T (MAIT) cells express a tissue repair transcriptomic program and promote skin wound healing when expanded. Herein, we use a human-like mouse model of full-thickness skin excision to assess the underlying mechanisms of MAIT cell tissue repair function. Single-cell RNA sequencing analysis suggested that skin MAIT cells already express a repair program at steady state. Following skin excision, MAIT cells promoted keratinocyte proliferation, thereby accelerating healing. Using skin grafts, parabiosis, and adoptive transfer experiments, we show that MAIT cells migrated into the wound in a T cell receptor (TCR)-independent but CXCR6 chemokine receptor-dependent manner. Amphiregulin secreted by MAIT cells following excision promoted wound healing. Expression of the repair function was probably independent of sustained TCR stimulation. Overall, our study provides mechanistic insights into MAIT cell wound healing function in the skin.
Ocular Manifestations of Graves' Disease: A Review
Authors: A P Weetman, A M McGregor, R Hall
Journal: Journal of the Royal Society of Medicine (1984)

Graves' ophthalmopathy is probably the most difficult management problem for the thyroidologist.This review aims to highlight recent advances in our knowledge of the condition in the fields of diagnosis, aetiology and treatment, but it will become apparent that much remains to be understood of the aetiology of Graves' ophthalmopathy which consequently impairs optimal management of the condition. DiagnosisThe presence of characteristic eye signs, namely periorbital oedema, chemosis, injection of the sclerae, exophthalmos, lid retraction and ophthalmoplegia in any combination, together with hyperthyroidism, present no difficulty in diagnosis.Problems may arise however if the patient is not and has not been thyrotoxic, in which case the condition is termed ophthalmic Graves' disease (OGD); in this subgroup the signs are often unilateral, raising the possibility of a retro-ocular space-occupying lesion in the differential diagnosis.
Innovations in Public Health Surveillance for Emerging Infections
Authors: Peng Jia, Shiyong Liu, Shujuan Yang
Journal: Annual Review of Public Health (2023)

Public health surveillance is defined as the ongoing, systematic collection, analysis, and interpretation of health data and is closely integrated with the timely dissemination of information that the public needs to know and upon which the public should act. Public health surveillance is central to modern public health practice by contributing data and information usually through a national notifiable disease reporting system (NNDRS). Although early identification and prediction of future disease trends may be technically feasible, more work is needed to improve accuracy so that policy makers can use these predictions to guide prevention and control efforts. In this article, we review the advantages and limitations of the current NNDRS in most countries, discuss some lessons learned about prevention and control from the first wave of COVID-19, and describe some technological innovations in public health surveillance, including geographic information systems (GIS), spatial modeling, artificial intelligence, information technology, data science, and the digital twin method. We conclude that the technology-driven innovative public health surveillance systems are expected to further improve the timeliness, completeness, and accuracy of case reporting during outbreaks and also enhance feedback and transparency, whereby all stakeholders should receive actionable information on control and be able to limit disease risk earlier than ever before.
Sustainable and Resilient Health Care in the Face of a Changing Climate
Authors: Jodi D. Sherman, Andrea J. MacNeill, Paul D. Biddinger, Ozlem Ergun, Renee N. Salas, Matthew J. Eckelman
Journal: Annual Review of Public Health (2023)

Climate change is a threat multiplier, exacerbating underlying vulnerabilities, worsening human health, and disrupting health systems' abilities to deliver high-quality continuous care. This review synthesizes the evidence of what the health care sector can do to adapt to a changing climate while reducing its own climate impact, identifies barriers to change, and makes recommendations to achieve sustainable, resilient health care systems.
Understanding the Neural Mechanisms of General Anesthesia from Interaction with Sleep–Wake State: A Decade of Discovery
Authors: Wei-Wei Bao, Shan Jiang, Wei-Min Qu, Wen-Xian Li, Chang-Hong Miao, Zhi-Li Huang
Journal: Pharmacological Reviews (2023)

The development of cutting-edge techniques to study specific brain regions and neural circuits that regulate sleep–wake brain states and general anesthesia (GA), has increased our understanding of these states that exhibit similar neurophysiologic traits. This review summarizes current knowledge focusing on cell subtypes and neural circuits that control wakefulness, rapid eye movement (REM) sleep, non-REM sleep, and GA. We also review novel insights into their interactions and raise unresolved questions and challenges in this field. Comparisons of the overlapping neural substrates of sleep–wake and GA regulation will help us to understand sleep–wake transitions and how anesthetics cause reversible loss of consciousness. <h3>Significance Statement</h3> General anesthesia (GA), sharing numerous neurophysiologic traits with the process of natural sleep, is administered to millions of surgical patients annually. In the past decade, studies exploring the neural mechanisms underlying sleep–wake and GA have advanced our understanding of their interactions and how anesthetics cause reversible loss of consciousness. Pharmacotherapies targeting the neural substrates associated with sleep–wake and GA regulations have significance for clinical practice in GA and sleep medicine.
Time to Change: A Systems Pharmacology Approach to Disentangle Mechanisms of Drug-Induced Mitochondrial Toxicity
Authors: Charlotte A. Hoogstraten, Jonathan J. Lyon, Jan A.M. Smeitink, Frans G.M. Russel, Tom J.J. Schirris
Journal: Pharmacological Reviews (2023)

An increasing number of commonly prescribed drugs are known to interfere with mitochondrial function, which is associated with almost half of all FDA black box warnings, a variety of drug withdrawals and attrition of drug candidates. This can mainly be attributed to a historic lack of sensitive and specific assays to identify the mechanisms underlying mitochondrial toxicity during drug development. In the last decade, a better understanding of drug-induced mitochondrial dysfunction has been achieved by network-based and structure-based systems pharmacological approaches. Here, we propose the implementation of a tiered systems pharmacology approach to detect adverse mitochondrial drug effects during preclinical drug development, which is based on a toolset developed to study inherited mitochondrial disease. This includes phenotypic characterization, profiling of key metabolic alterations, mechanistic studies, and functional in vitro and in vivo studies. Combined with binding pocket similarity comparisons and bottom-up as well as top-down metabolic network modeling this tiered approach enables identification of mechanisms underlying drug-induced mitochondrial dysfunction. After validation of these off-target mechanisms, drug candidates can be adjusted to minimize mitochondrial activity. Implementing such a tiered systems pharmacology approach could lead to a more efficient drug development trajectory due to lower drug attrition rates and ultimately contribute to the development of safer drugs. <b>Significance Statement</b> Many commonly prescribed drugs adversely affect mitochondrial function, which can be detected using phenotypic assays. However, these methods provide only limited insight into the underlying mechanisms. In recent years, a better understanding of drug-induced mitochondrial dysfunction has been achieved by network-based and structure-based system pharmacological approaches. Their implementation in preclinical drug development could reduce the number of drug failures, contributing to safer drug design.
Turn On, Tune In, Turnover! Target Biology Impacts In Vivo Potency, Efficacy, and Clearance
Authors: Johan Gabrielsson, Stephan Hjorth
Journal: Pharmacological Reviews (2023)

Even though significant efforts have been spent in recent years to understand and define the determinants of <i>in vivo</i> potency and clearance, important pieces of information are still lacking. By introducing <i>target</i> turnover into the reasoning, we open up to further the understanding of central factors important to the optimization of translational dose-concentration-response predictions. We describe: <b><i>i) </i></b>new (9open9 model) expressions of the <i>in vivo</i> potency and efficacy parameters which embody target turnover, binding and complex kinetics, also capturing full, partial, and inverse ago­nism, and antagonism, <b><i>ii)</i></b><i></i>a detailed examination of 9open9 models to show what potency and efficacy parameters have in common and how they differ, and, <b><i>iii)</i></b><i></i>a comprehensive literature review showing that target turnover rate varies with age, species, tissue/subregion, treatment, disease state, hormonal and nutritional state, and day-night cycle. The new 9open9 model expression which integrates system- and drug properties, shows that: fractional turnover rates rather than the absolute target or ligand-target complex expression determine necessary drug exposure via <i>in vivo</i> potency; absolute ligand-target expression determines the need of drug, based on the transduction Rho<i></i>and <i>in vivo</i> efficacy parameters; the free enzyme concentration determines clearance and maximum metabolic rate; the fractional turnover rate determines time to equilibrium between substrate, free enzyme and complex; properties of substrate, target, and complex demonstrate non-saturable metabolic behavior at equilibrium; non­linear processes previously referred to as capacity- and time-dependent kinetics may occasionally have been disequilibria; and, the 9open9 model may pinpoint why some subjects differ in their demand of drug. <b>Significance Statement</b> 'Understand the target turnover' is a central tenet in many translational dose-concentration-response predictions. New 'open' model expressions of <i>in vivo</i> potency, efficacy parameter and clearance are derived and anchored onto a comprehensive literature review showing that target turnover rate varies with age, species, tissue/subregion, treatment, disease, hormonal and nutritional state, day-night cycle, and more. Target turnover concepts will therefore significantly impact fundamental aspects of pharmacodynamics and pharmacokinetics, thereby also the basics of drug discovery, development, and optimization of clinical dosing.
Corrigendum to “Bioinspired nanovehicle of furoxans-oxaliplatin improves tumoral distribution for chemo-radiotherapy” [Journal of Controlled Release 353 (2023) 447–461]
Authors: Xindi Qian, Yuqi Wang, Honglei Xie, Chen Wang, Jie Li, Ying Lei, Huanzhen Liu, Yao Wu, Yaping Li, Zhiwen Zhang
Journal: Journal of Controlled Release (2023)
Mitochondrial signalling and homeostasis: from cell biology to neurological disease
Authors: Jack J. Collier, Monika Oláhová, Thomas G. McWilliams, Robert W. Taylor
Journal: Trends in Neurosciences (2023)

Efforts to understand how mitochondrial dysfunction contributes to neurodegeneration have primarily focussed on the role of mitochondria in neuronal energy metabolism. However, progress in understanding the etiological nature of emerging mitochondrial functions has yielded new ideas about the mitochondrial basis of neurological disease. Studies aimed at deciphering how mitochondria signal through interorganellar contacts, vesicular trafficking, and metabolic transmission have revealed that mitochondrial regulation of immunometabolism, cell death, organelle dynamics, and neuroimmune interplay are critical determinants of neural health. Moreover, the homeostatic mechanisms that exist to protect mitochondrial health through turnover via nanoscale proteostasis and lysosomal degradation have become integrated within mitochondrial signalling pathways to support metabolic plasticity and stress responses in the nervous system. This review highlights how these distinct mitochondrial pathways converge to influence neurological health and contribute to disease pathology.
Racial and Ethnic Disparities in Opioid Access and Urine Drug Screening Among Older Patients With Poor-Prognosis Cancer Near the End of Life
Authors: Andrea C. Enzinger, Kaushik Ghosh, Nancy L. Keating, David M. Cutler, Cheryl R. Clark, Narjust Florez, Mary Beth Landrum, Alexi A. Wright
Journal: Journal of Clinical Oncology (2023)

To characterize racial and ethnic disparities and trends in opioid access and urine drug screening (UDS) among patients dying of cancer, and to explore potential mechanisms.
Prospective Multicenter Diagnostic Performance of Technologist-Performed Screening Breast Ultrasound After Tomosynthesis in Women With Dense Breasts (the DBTUST)
Authors: Wendie A. Berg, Margarita L. Zuley, Thomas S. Chang, Terri-Ann Gizienski, Denise M. Chough, Marcela Böhm-Vélez, Danielle E. Sharek, Michelle R. Straka, Christiane M. Hakim, Jamie Y. Hartman, Kimberly S. Harnist, Cathy S. Tyma, Amy E. Kelly, Uzma Waheed, Golbahar Houshmand, Bronwyn E. Nair, Dilip D. Shinde, Amy H. Lu, Andriy I. Bandos, Jeremy M. Berg, Nicole B. Lettiere, Marie A. Ganott
Journal: Journal of Clinical Oncology (2023)

To assess diagnostic performance of digital breast tomosynthesis (DBT) alone or combined with technologist-performed handheld screening ultrasound (US) in women with dense breasts.